Simplified process for sterilizing semi-solid to solid preparations based on oligomers of lower hydroxycarboxylic acids or their salts

ABSTRACT

Described is a process for the simplified sterilization, by heating to high temperatures, of semisolid to solid preparations based on oligomers of lower carboxylic acids or their salts, as well as their transformation products with molecular weight regulating components, the preparations also optionally including biocompatible minerals. According to the invention, the materials to be sterilized are subjected to the action of high frequency oscillations in the microwave range (microwaves).

BACKGROUND OF THE INVENTION

DE-OSS 32 29 540 and 37 16 302 relate to resorbable waxes formechanically stanching blood on hard, body tissue, particularly onbones, which are characterized in that they consist of polyesteroligomers of lower hydroxycarboxylic acids which are viscous to solidand wax-like at body temperature. Corresponding polyesters, oligomers oflactic acid and/or glycolic acid are described as particularly suitable.By virtue of their structure, these waxes can be degraded by the body'sown metabolic mechanisms, the degradation rate being adjustable in knownmanner. The preferred waxes have average molecular weights in the rangefrom about 200 to 1,500 and, more particularly, in the range from about300 to 1,000.

Monofunctional and/or difunctional alcohols and/or carboxylic acids areused to regulate the average molecular weight, particular significancebeing attributed to glycerol as a polyfunctional alcohol. In anotherimportant embodiment, the resorbable materials are almost completelyfreed from free carboxyl groups. This may be done either by specificpurification, as described for example in the publications cited above,or by salt formation at carboxyl groups which are still present in thereaction product or which have been specifically added, for examplethrough free hydroxycarboxylic acids of the type mentioned.

Thus, earlier German patent applications P 38 25 211.2 (D 8293) and P 3826 915.5 (D 8265) describe compositions based on oligomers of thedescribed type which are characterized by a content of body-compatiblesalts of organic and/or inorganic acids, corresponding salts beingformed by reaction of any free carboxyl groups still present in theoligomer wax and/or being homogeneously incorporated in the wax as addedsalts. In the second of these two earlier applications, this concept ofbody-compatible and resorbable oligomer compounds, particularly based onglycolic acid and/or lactic acid, is widened to the extent that at leastpartly resorbable bone substitutes and/or bone composites andauxiliaries for fixing prosthesis material in living bone tissue aredescribed. The oligomers used for this purpose may have averagemolecular weights in a broader range of from about 200 to 10,000 g/moland, more particularly, in the range from about 300 to 5,000 g/mol.Mixtures of oligomer resins containing ceramic materials in preferablyhomogeneous distribution are described as particularly suitable. Theseceramic materials, which are present in particular in powder and/orgranular form, may be resorbable or even non-resorbable in the body,particular significance being attributed to bioactive ceramic materials,above all based on calcium phosphate compounds. Suitable calciumphosphates are, for example, hydroxyl apatite and/or tricalciumphosphate.

The described oligomer compounds are produced by a polycondensationand/or polyaddition reaction carried out at elevated temperature,generally in the presence of small quantities of mildly acidiccatalysts. The ceramic materials and/or salts optionally used are alsonormally incorporated at elevated temperature, generally via the meltphase of the organic resins.

DESCRIPTION OF THE INVENTION

For practical application in the field of surgery, the compositions inquestion generally have to lend themselves to portion-controlled packingand, at the same time, to complete sterilization. The problem addressedby the present invention was to satisfy these requirements as simply aspossible for materials of the described type. The technical solution tothis problem is based on the known principle of germ destruction byheating the material to be sterilized to sufficiently high temperatures.The teaching of the invention is crucially dependent upon the choice ofthe technical said with which temperature control is undertaken andmanaged for at least considerable periods of the sterilization process.The new teaching is based on the discovery that it is possible to heatthe material to be sterilized to the necessary temperatures in apredeterminable manner by the action of high-frequency electromagneticvibrations in the microwave range--known generally as "microwaves".

Accordingly, the present invention relates to a process for thesterilization of semisolid to solid preparations based on oligomers oflower hydroxycarboxylic acids or salts or reaction products thereof withmolecular weight regulators, more particularly monofunctional and/orpolyfunctional alcohols or corresponding carboxylic acids, which mayeven be present in admixture with body-compatible minerals, by heatingto elevated temperatures, characterized in that the material to besterilized is exposed to the effect of microwaves.

The application of high-frequency electromagnetic vibration in the uppermegahertz range to the middle gigahertz range has been increasingly putinto practice in recent years. One well-known example of this from thedomestic field is the microwave oven which is used for the rapid andthorough heating and, optionally, the preliminary defrosting ofprecooked foods. The selected microwave radiation in the lower to middlegigahertz range, for example in the range from about 0.1 to 300 GHz andpreferably in the range from about 0.1 to 30 GHz, excites the watermolecules present in the material to be heated and thus heats thewater-containing material from inside outwards. The ability of theradiation to penetrate into the interior of the material to be heated isgreater at lower frequencies than at higher frequencies within the rangementioned, cf. for example Mikrowellen (Gunter Nemitz, Munchen, 1980),page 155.

The use of microwaves has also been proposed in related fields, forexample for heating damp textiles, particularly in washing and dryingprocesses. In every case, however, the microwaves are used inwater-containing, moist material.

On the basis of their production, oligomer resins of the type targetedby the present invention are to be regarded as anhydrous materials.Known materials of this type include not only polycondensation resinshaving comparatively limited average molecular weights, as targeted bythe present invention, but also solid polymers of this type having verymuch higher molecular weights. Attempts to heat, let alone sterilize,solid high molecular weight materials of this type, for examplebody-resorbable filament material based on high polymers of glycolicacid and/or lactic acid, by the action of microwaves have beenunsuccessful. It would appear that inadequate resonance is initiatedbetween inherently polar parts of the molecule and the radiation.

Surprisingly, the situation takes on a completely different appearancewhen resins of the type described in the previously published patentsand patent applications cited at the beginning, or in older patents andpatent applications, are exposed to the effect of microwaves. Theradiation of energy in a domestic microwave oven results incomparatively rapid heating of the resins, the temperature of at leastabout 100° C. that is crucial to sterilization being reached morequickly, the more rapidly the softening and/or liquefaction of theoligomers accompanying this heating occurs. In addition, the radiationof equal amounts of energy into an initially wax-like and solid materialwhich becomes increasingly soft to liquid at increasing temperaturesshows that the interaction between the material to be heated and theradiated energy is more effective, the more mobile in character theresin becomes as a result of the increase in temperature. The increasesin temperature which the sample of material undergoes and which can beadjusted per predetermined unit of energy and time become greater withincreasing softness of the material sample during the stepwisetransition from the solid state to the molten state.

One explanation of the suitability of microwaves for thermalsterilization of the class of resins targeted by the invention could bethat, even with material samples that are initially wax-like to solid inappearance, sufficient amounts of comparatively short-chain oligomersare present to enter into an interaction with the radiated energy, beingheated in the process, softening their immediate surroundings andleading to an increase in the responsive resin volume. Another crucialfactor in this regard would appear to be the fact that not only do themicrowaves attack the outer regions of the material to be heated, theyalso penetrate throughout the material as a whole. As a result, thematerial is completely heated from inside outwards. It is clear that theconditions essential for solving the problem of sterilization addressedby the invention are thus established. This applies not only tomaterials which are formed as such by the oligomers, for example ofglycolic acid and/or lactic acid, but also to the mixed productscontaining ceramic components which are mentioned in the earlierapplications cited above. Where resin and ceramic material--preferablyin finely divided form--are thoroughly mixed, even comparatively thicklayers of material are heated throughout and, hence, sterilized by theaction of microwaves according to the invention. It can be seen that, inpractice, this considerably simplifies the provision ofportion-controlled packs in fully sterilized form.

According to the invention, therefore, it is thus possible, for example,to subject bone waxes or materials intended as adhesion said for medicalpurposes to sterilization in individual portions and, more particularly,in the form of at least substantially sealed portion packs. The materialto be sterilized is accommodated in the pack which withstands the actionof microwaves and allows them to pass through. It is generally knownthat plastics, for example polyolefins, are particularly suitable forthis purpose and are already being widely used, for example, for theportion-controlled packing of so-called instant meals for heating inmicrowave ovens.

The oligomer materials to be subjected to the process should preferablybe at least viscous and free-flowing at temperatures in the range inwhich the sterilizing treatment is carried out. Bone waxes and adhesivesof the described type, particularly those having average molecularweights in the ranges mentioned, are normally molten and free-flowing attemperatures above 100° C., for example at temperatures of up to 130° C.

In one particular embodiment of the invention, it may be useful toactivate preparations which are solid at room temperature and which,initially, show little response to the effect of high-energy radiationof the type in question by conventionally preheating materials of thistype to a limited extent. It may be useful in this regard to preheat atleast parts of the particular samples of material to be sterilized untilthey begin to soften and then to expose the material thus pretreated tothe effect of microwaves. However, a combined temperature treatment suchas this is necessary only in special cases.

In the process according to the invention, the microwave radiation maybe applied intermittently or continuously and may cover an entireprocess stage or only parts thereof. The temperature to be establishedis controlled by the choice of the intensity and duration of themicrowave radiation. By intermittent irradiation at comparatively lowpower levels, for example up to at most 200 watts, it is possible toestablish moderate temperatures and/or to keep to a predeterminedtemperature range for a relatively long period. In the heating phase ofthe process, it can be useful to apply comparatively high power levels,for example up to 1,000 watts, either continuously or intermittently.

The residence time of the material to be sterilized in the predeterminedsterilization temperature range is determined by existing knowledge ofsterilization processes of the type required in the context of theinvention. For example, sterilization can be obtained by heating totemperatures of at least 100° C. and preferably to temperatures of 110°C. for the period required for safe destruction of unwanted germs. Forexample, temperatures in the range above 120° C. to 180° C. applied fora few minutes or even longer are suitable.

To carry out the process according to the invention, it is oftensufficient to apply a predetermined amount of energy to the quantity ofmaterial to be sterilized, which is preferably accommodated in the atleast substantially sealed portion pack, and then to leave thecorrespondingly heated sample of material to cool in a regulated ordelayed process. If necessary, the particular portion pack may then becompletely sealed without further contact with the material accommodatedtherein.

EXAMPLES

The microwave generator used is a commercially available microwave ovenof the "Siemens" brand which has a timed power input graduated asfollows: 90 W, 180 W, 360 W and 600 W. The radiated energy has afrequency of 2.45 GHz.

The material samples characterized in detail in the following Examplesare present in quantities of approximately 30 g in unsealed glassbottles which, to carry out the tests, are successively placed at thecenter of the heating zone.

The starting temperature of all material samples is 21° C., unlessotherwise specifically stated. Microwave energy is applied continuouslyor intermittently as described in the Examples (selected energy inputand duration of the particular heating phase). Immediately after aheating phase, the temperature in the upper part of the particularmaterial sample is determined by insertion of a laboratory mercurythermometer. The following heating phase(s) are each carried outimmediately after the temperature measurement.

The chemical composition of the oligomers investigated and theirphysical character both before and after the application of microwaveenergy are shown in the following Examples.

EXAMPLE 1 Reaction product based on glycerol, glycolic acid and oleicacid in a molar ratio of 1:3:3: viscous and free-flowing at roomtemperature

    ______________________________________                                                                      Temperature of the                              Heating                                                                              Energy input                                                                              Heating time                                                                             irradiated material                             stage  (W)         (secs.)    °C.                                      ______________________________________                                        1.     600         30         59                                              2.     600         15         75                                              ______________________________________                                    

The material sample is cooled to an initial temperature of 30° C. andsubjected to another two-stage heating cycle. The following results areobtained.

    ______________________________________                                                                      Temperature of the                              Heating                                                                              Energy input                                                                              Heating time                                                                             irradiated material                             stage  (W)         (secs.)    °C.                                      ______________________________________                                        1.     600         60          78                                             2.     600         60         131                                             ______________________________________                                    

EXAMPLE 2

Reaction product based on glycerol, glycolic acid, lactic acid and oleicacid in a molar ratio of 1:6:6:3. The starting material is highlyviscous at room temperature.

    ______________________________________                                                                      Temperature of the                              Heating                                                                              Energy input                                                                              Heating time                                                                             irradiated material                             stage  (W)         (secs.)    °C.                                      ______________________________________                                        1.     600         45         74                                              ______________________________________                                    

The heated material is a thin liquid. It is cooled to a startingtemperature of 32° C. and then resubjected to two-stage heating with thefollowing results:

    ______________________________________                                                                      Temperature of the                              Heating                                                                              Energy input                                                                              Heating time                                                                             irradiated material                             stage  (W)         (secs.)    °C.                                      ______________________________________                                        1.     600         60          76                                             2.     600         45         113                                             ______________________________________                                    

EXAMPLE 3

A condensation product based on glycerol and lactic acid in a molarratio of 1:4, which is viscous at room temperature, is exposed for 60seconds to a single-stage power input of 600 W. The final temperaturereached is 158° C. The material sample is a thin liquid.

EXAMPLE 4

A viscous starting material based on glycerol and lactic acid in a molarratio of 1:12 is exposed to two-stage heating. The operating conditionsand results are as follows:

    ______________________________________                                        Power input                                                                             Time     Temperature                                                (W)       (secs.)  °C.  Resin consistency                              ______________________________________                                        180       60        38         Viscous                                        600       60       138         Thinly liquid                                  ______________________________________                                    

EXAMPLE 5

A solid, wax-like condensation product based on tallow alcohol andlactic acid in a molar ratio of 1:17 is heated by exposure to a powerinput of 600 W in three stages. The first stage lasts 50 seconds whilethe second and third stages each last 60 seconds.

After the first heating stage, the material sample is so solid that itstemperature cannot be measured. After the second heating stage, thematerial sample has softened to such an extent that the thermometer canbe inserted into the wax mass. The temperature determined at this stageis 55° C. At the end of the third heating stage, the material is in aninhomogeneous and partly molten state. The temperature in the moltenparts is 105° C.

EXAMPLE 6

A solid wax-like condensation product based on glycerol and glycolicacid in a molar ratio of 19 is exposed twice for 30 seconds to a powerinput of 600 W.

Result of the first treatment stage: the material sample is still mainlysolid, but has melted to paste-like state in the middle. A temperatureof 74° C. is measured in the melted parts. On completion of the secondheating stage, the material is almost completely molten. The temperaturemeasured in the melt is 133° C.

EXAMPLE 7

A viscous/solid condensation product based on glycerol/glycolicacid/lactic acid in a molar ratio of 15:1 is exposed for 45 seconds to asingle-stage power input of 600 W. A thinly liquid melt having atemperature of 126° C. is formed.

EXAMPLE 8

A viscous/solid material based on glycerol, glycolic acid and lacticacid in a molar ratio of 1:2:12 is exposed for 60 seconds to a powerinput of 360 W and then for another 60 seconds to a power input of 600W.

After the first heating stage, the material sample is viscous and has atemperature of about 38° C. The thinly liquid, molten material obtainedin the second heating stage has a temperature of 162° C.

EXAMPLE 9

A glycerol/glycolic acid ester in a molar ratio of 1:3 (consistency:viscous) is exposed for 70 seconds to a single power input of 360 W. Athinly liquid melt having a temperature of 131° C. is formed.

EXAMPLE 10

An oligomeric condensation product based on glycerol, glycolic acid andlactic acid in a molar ratio of 1:6:6 is subjected to a six-stageheating cycle, power input 600 w in each stage, in the following timesequence:

1st stage: 45 secs., resin unchanged, solid and lukewarm

2nd stage: 30 secs., viscous consistency, 39° C.

3rd stage: 20 secs., resin partly molten, temperature in the molten zone84° C.

4th stage: 10 secs., more melting, temperature in the molten zone 91° C.

5th stage: 10 secs., completely molten and viscous, temperature 94° C.

6th stage: 20 secs., thinly liquid, dripping melt, temperature 119° C.

What is claimed is:
 1. A process for the sterilization of a semisolid tosolid composition consisting essentially of:(A) oligomers having averagemolecular weights in the range from about 200 to about 10,000, saidoligomers consisting essentially of the residues of monomers selectedfrom the group consisting of lower hydroxycarboxylic acids, saltsthereof, and mixtures thereof, and, optionally, also of residues ofmolecular weight regulator monomers; and, optionally (B) body-compatibleminerals,said process comprising heating said composition to asterilization temperature range and maintaining said composition withinthe sterilization temperature range for an effective time to destroy anyunwanted germs present in said composition, said heating beingaccomplished by irradiating said composition with microwaves.
 2. Aprocess as claimed in claim 1, wherein the composition sterilized by theprocess is viscous to wax-like at body temperature.
 3. A process asclaimed in claim 1, wherein said composition is sterilized whilecontained in a portion-controlled pack.
 4. A process as claimed dinclaim 1, wherein the composition that is sterilized is viscous andfree-flowing in the sterilization temperature range.
 5. A process asclaimed in claim 1, wherein the compositions sterilized by the processis solid at room temperature and is exposed to the microwave radiationafter being preheated.
 6. A process as claimed din claim 1, wherein thecomposition to be sterilized is continuously irradiated with microwavesfor each of at least two distinct periods of time, said periods of timebeing separated by a time interval during which composition to besterilized is not irradiated with microwaves.
 7. A process as claimeddin claim 1, wherein said oligomers consist essentially of the residuesof monomers selected from the group consisting of lowerhydroxycarboxylic acids, salts thereof, alcohols, carboxylic acids otherthan lower hydroxycarboxylic acids, and mixtures thereof.
 8. A processas claimed in claim 2, wherein said oligomers consist essentially ofresidues of (i) monomers selected from the group consisting of glycolicacid, lactic acid, derivatives thereof, and mixtures of any two or moreof these components and (ii) monomers selected form the group consistingof alcohols other than hydroxycarboxylic acids, carboxylic acids othersthan hydroxycarboxylic acids, and mixtures thereof.
 9. A process asclaimed din claim 8, wherein said composition is sterilized whilecontained in an at least substantially sealed pack.
 10. A process asclaimed in claim 7, wherein said composition is sterilized whilecontained in an at lest substantially sealed pack.
 11. A process asclaimed in claim 2, wherein said composition is sterilized whilecontained in an at least substantially sealed pack.
 12. A process asclaimed in claim 11, wherein the composition that is sterilized by theprocess is viscous and free-flowing in the sterilization temperaturerange.
 13. A process as claimed in claim 10, wherein the compositionthat is sterilized by the process is viscous and free-flowing in thesterilization temperature range.
 14. A process as claimed in claim 9,wherein the composition that is sterilized by the process is viscous andfree-flowing in the sterilization temperature range.
 15. A process asclaimed din claim 8, wherein the composition that is sterilized by theprocess is viscous nd free-flowing in the sterilization temperaturerange.
 16. A process as claimed in claim 7, wherein the composition thatis sterilized by the process is viscous and free-flowing in thesterilization temperature range.
 17. A process as claimed in claim 3,wherein the composition that is sterilized by the process is viscous andfree-flowing in the sterilization temperature range.
 18. A process asclaimed in claim 2, wherein the composition that is sterilized by theprocess is viscous and free-flowing in the sterilization temperaturerange.
 19. A process as claimed in claim 8, wherein the composition tobe sterilized is continuously irradiated with microwaves for each of atlest two distinct periods of time, said periods of time being separatedby a time interval during which the composition to be sterilized is notirradiated with microwaves.
 20. A process as claimed in claim 7, whereinthe composition to be sterilized is continuously irradited withmicrowaves for each of at least two distinct periods of time, saidperiods of time being separated by a time interval during whichcomposition to be sterilized is not irradiated with microwaves.